There is growing evidence that the N-methyl-D-aspartate (NMDA) class of the glutamate receptor modulates the effects of a number of drugs of abuse. Therefore, it is likely that a deeper understanding of interactions of the NMDA system with drugs of abuse will inform the search for treatment interventions, both in relationship to drug dependence and pain modulation. The proposed experiments explore the mechanisms underlying interactions between the NMDA system and opioid analgesics using an integrative strategy that combines genetic, pharmacological and behavioral approaches. The genetic approach employs an animal model of NMDA deficiency that consists of partial deletion of the gene encoding the essential NR1 subunit of the NMDA receptor (NR1-/- mice). The pharmacological approach explores interactions between drugs of abuse and a range of NMDA antagonists in mice of the C57BL/6 background strain. Both the genetic and the pharmacological approaches are used to investigate several prominent behavioral effects of opioid analgesics, namely their antinociceptive, conditioned and reinforcing effects. Specific Aim 1 examines the role of NMDA receptors in opioid antinociception and tolerance, employing two different antinociceptive assays: the hot plate procedure and the tail withdrawal procedure. Specific Aim 2 investigates the role of NMDA receptors in the conditioned effects of morphine and other opioid analgesics using the conditioned place preference procedure (CPP) and Specific Aim 3 investigates in the reinforcing effects of opioid agonists using a drug self-administration procedure. Preliminary experiments indicate the feasibility of using these approaches in our own laboratory. Collectively, the specific aims test the hypothesis that the antinociceptive and reinforcing effects of morphine and other opioid analgesics are altered in NR1-/- mice as compared to WT controls and that morphine's effects are altered by the administration of selective NMDA antagonists in two background strains of mice, C57BL/6 and 129/SvEv.